PROCESS FOR PREPARATION OF 5H DIBENZO[a,d] CYCLOHEPTENE DERIVATIVES

ABSTRACT

A process for preparation of protriptyline hydrochloride from 5-dihydrobenzocycloheptatriene of formula (1) by coupling with chloropropyl alcohol in the presence of excess n-butyl Lithium in tetrahydrofuran under inert atmosphere, followed by preparation of mesylate derivative of formula (3) and finally the nucleophilic displacement of the mesylate group by reacting methylamine solution in methanol to give protriptyline free base of the formula (4). Also the present process reveals the hydrochloride salt formation and purification of the same to give pure pharmaceutical grade protriptyline hydrochloride with impurities less than 0.1% w/w.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/609,075, filed Dec. 11, 2006, pending, the entire disclosure of whichis hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to processes for preparingdibenzocycloheptene compounds and specifically to novel processes forthe production of 5H-dibenzo[a,d] cycloheptene derivatives which aresubstituted at 5-position, more particularly N-methyl-5H-dibenzo(a,d)-cycloheptene-5-propanamine hydrochloride.

Protriptyline hydrochloride is a dibenzocycloheptatriene derivative withthe chemical name N-methyl-5H-dibenzo (a,d)-cycloheptene-5-propanaminehydrochloride. Protriptyline hydrochloride is used as an antidepressantunder the trade name VIVACTIL™ and is supplied as tablets in strengthsof 5 and 10 mg.

U.S. Pat. No. 5,932,767 assigned to Merck & Co., Inc. discloses thepreparation of protriptyline from 5-dihydrodibenzocycloheptatriene, bydeprotonation, followed by reaction at low temperatures with1,3-bromochloropropane to give the5-(chloropropyl)-dibenzocycloheptatriene, which is reacted withmethylamine in a displacement reaction to give the protriptylineproduct.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a simple,cost-effective and reliable process for the preparation of protriptylinehydrochloride.

Another object of the invention is to provide a simple, cost-effectiveand reliable process for preparation of the intermediate3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2).

Still another object of the invention is to provide a simplifiedprocedure for the isolation of3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2)hereinbelow which is desired for generating a compound having formula(3) hereinbelow having a suitable leaving group such as mesylate,tosylate, besylate or acetyl. In one embodiment this achieved usingmethane sulfonyl chloride.

Yet another object of the invention is to provide a process whereby thecompound of formula (3) which upon reaction with methyl amine gives riseto the compound 5-(N-methyl-aminopropyl) dibenzocycloheptatriene offormula (4). These and other aspects of the invention will be apparentto those skilled in the art.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following description, for purposes of explanation, specificnumbers, materials and configurations are set forth in order to providea thorough understanding of the invention. It will be apparent, however,to one having ordinary skill in the art that the invention may bepracticed without these specific details. In some instances, well-knownfeatures may be omitted or simplified so as not to obscure the presentinvention. Furthermore, reference in the specification to phrases suchas “one embodiment” or “an embodiment” means that a particular feature,structure or characteristic described in connection with the embodimentis included in at least one embodiment of the invention. The appearancesof phrases such as “in one embodiment” in various places in thespecification are not necessarily all referring to the same embodiment.

In accordance with one embodiment the present invention relates to novelprocesses for the production of 5H-dibenzo[a,d] cycloheptene derivativeswhich are substituted at the 5-position. In one embodiment,N-methyl-5H-dibenzo (a,d)-cycloheptene-5-propanamine hydrochloride isprepared by reacting 5-dihydro dibenzocycloheptatriene with chloropropyl alcohol in the presence of an excess of n-butyl lithium solution.The resulting product is converted to a mesylate, tosylate, besylate oracetyl derivative, followed with a nucleophilic displacement reactionusing methylamine in methanol, water or tetrahydrofuran. The resultingproduct is then converted to protryptilene hydrochloride.

Scheme

The following provides a process for the production of protriptylinehydrochloride of formula (5):

Experimental Procedures

Thus, in accordance with an embodiment the present invention a firststep involves condensation of the starting material of the formula (1)to 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2).

In one example the process for this transformation involves inertreaction between excess equivalent of n-butyl lithium and chloropropylalcohol with starting material of formula (1) at −15° C. to −20° C. indry tetrahydrofuran. After 4.0 hours reaction, reaction mass wasquenched with water. Upon distillation of organic layer gives crude3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2).Crude product upon high vacuum distillation gives pure3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2) in65-75% yield range.

The second step of this process involves formation of formula (3) from3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2).

wherein R denotes a mesylate, tosylate, besylate or acetyl group.

In one example this reaction was carried out in inert conditions.3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2) wasdissolved in dry tetryhydrofuran and cooled down to 0° C.-5° C. Triethylamine (1.5 eq.) was added followed by methane sulfonyl chloride (1.2eq.) drop wise at 0° C.-5° C. After addition, the reaction masstemperature was raised to room temperature. The reaction mass wasquenched with water and the organic layer was washed with brinesolution. The solvent was distilled out under reduced pressure whichyielded a light yellow color viscous compound, namely, the mesylatederivative of formula (3) in 90-95% yield.

The third step of the invention involves nucleophilic displacement ofthe mesylate group in formula (3) with methylamine solution in methanolwhich gives rise to the compound 5-(N-methyl-aminopropyl)dibenzocycloheptatriene of formula (4).

In one example of this step the mesylate derivative of formula (3) andmethylamine solution were mixed in methanol and refluxed for 2.0 hours.After 2.0 hours the solvent was distilled out under reduced pressure.The remaining residue was dissolved in water and pH was adjusted to 2.0to 3.0 with concentrated HCL. One isopropyl ether washing was given tothe aqueous solution. The pH was adjusted to 6.0 and given one isopropylether washing. pH was adjusted to 7.0 and given one more IPE wash. Theaqueous layer was basified with ammonium hydroxide and extracted withdichloromethane. The organic layer was washed with water followed bybrine solution and dried using sodium sulfate in the solution. Thesolution was filtered with sodium sulfate and washed withdichloromethane. To the filtrate charcoal was added and stirred for 1hour at 25-30° C. The reaction mass was filtered through a celite bedand washed with dichloromethane.

The fourth step of the present process invention involves conversion ofthe 5-(N-methyl-aminopropyl) dibenzocycloheptatriene (4) toprotriptyline hydrochloride (5) using ether HCl and dichloromethane.

In one example this step was carried out by distilling thedichloromethane from the 5-(N-methyl-aminopropyl)dibenzocycloheptatriene formula (4) residue under reduced pressure.Fresh dichloromethane was added to dissolve the residue. The solutionwas cooled to 5° C. to 10° C. After addition, dichloromethane wasdistilled out under vacuum. The residue was co-distilled twice withethyl acetate. To the residue was added ethyl acetate and the reactionmass cooled to room temperature. The reaction mass was stirred for 5-6hours at room temperature. The solid formed was filtered and washed withethyl acetate and vacuum dried.

Purification of crude protriptyline hydrochloride was carried out bymaking a slurry by taking the above wet cake in 4 volumes of toluene andheated to 80° C. with stirring. At the same temperature the slurry wasstirred for a half-hour. The reaction mass was cooled to roomtemperature and the solid filtered and washed with acetone. The wet cakewas subjected to two acetone hot Teachings. This yielded a pureprotriptyline hydrochloride with chemical name N-methyl-5H-dibenzo(a,d)-cycloheptene-5-propanamine hydrochloride of formula (5) in 20-30%yield range to afford 99.95% to 100.00% pure material by HPLC.

EXAMPLES 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula(2)

200 gm of starting material of formula (1) was charged into a 10 Lthree-neck flask containing dried tetrahydrofuran, under nitrogenatmosphere. The reaction mass was cooled to −15° C. to −20° C. n-butyllithium solution 4.0 eq. (1.6 M in hexane) was added drop wise. Afteraddition, the reaction mass was stirred for 2.0 hours at −10° C. to −15°C. To the reaction mass was added 3-chloropropyl alcohol 1.05 eq. dropwise at −15 to −20° C. After addition, the reaction mass was stirred for2.0 hours at −10° C. to −15° C. Completion of the reaction was checkedby TLC. The reaction mass was quenched with water. The organic layer waswashed with brine solution and dried with sodium sulfate. Solvent wasremoved under reduced pressure to afford crude light yellow colorviscous liquid product 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-olof the formula (2) in 300.0 gm yield.

Purification of crude 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol ofthe formula (2)

The crude product 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of theformula (2) was subjected to high vacuum fractional distillation. Thefirst fraction was collected at vapor temperature 48° C.-55° C. Thesecond fraction was collected at vapor temperature 120° C.-165° C. Theproduct fraction was collected at vapor temperature 165° C.-195° C. toafford light green color to colorless product of3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2) in135-145 gm (50%) yield.

Mesylate derivative of formula (3)

3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol of the formula (2)(100.0 gm) was charged into a 2.0 L single neck flask and dissolved indried tetrahydrofuran under nitrogen atmosphere and Cooled to 0° C.-5°C. Triethyl amine (84.5 mL, 1.5 eq.) was added drop wise at 0° C.-5° C.followed by drop wise addition of methane sulfonyl chloride (37.3 mL,1.2 eq.) at 0° C.-5° C. The reaction mass temperature was raised to roomtemperature. Completion of the reaction was checked by TLC. The reactionmass was quenched with water and a brine wash was given. The organiclayer was dried over sodium sulfate. Solvent was removed under reducedpressure to afford light yellow color viscous product mesylatederivative compound of formula (3) (130 to 135 gm).

5-(N-methyl-aminopropyl) dibenzocycloheptatriene of Formula (4)

The mesylate derivative of formula (3) 100.0 gm was charged into a 2.0 Lsingle neck flask. 582 ml (20 eq) of methylamine solution in methanol(30%) was added into the flask. The reaction mass was heated to refluxtemperature (65°-70° C.) and stirred at reflux temperature for 2.0hours. Completion of the reaction was checked by TLC. The solvent wasremoved under reduced pressure. The residue was dissolved in water at pH3.0 and given an isopropyl ether wash. The isopropyl ether wash wasrepeated at pH 6.0 and again at pH 7.0. The aqueous layer was basifiedand extracted with dichloromethane. The organic layer was washed withwater, followed by brine solution and dried over sodium sulfate toobtain 5-(N-methyl-aminopropyl) dibenzocycloheptatriene of formula (4).

Protriptyline hydrochloride of Formula (5)

Charcoal (15 gm) was added to 5-(N-methyl-aminopropyl)dibenzocycloheptatriene of formula (4) and stirred for 1.0 hour at 25°C. to 30° C. The contents of the flask were filtered through a celitebed and washed with dichloromethane. The dichloromethane solution wasdistilled atmospherically 40° C. to 45° C. up to half of the volume. Thereaction mass was cooled to 20° C.-25° C. and chilled to 5° C. to 10° C.37.0 mL of ether HCl (15-20%) was added drop wise into the reaction massat 5° C. to 10° C. After this addition the dichloromethane was distilledout completely under vacuum. To the reaction mass ethyl acetate (300 mL)was added and the reaction mass was cooled to 25° C. to 30° C. Thereaction mass was further stirred for 5-6 hours at 25° C. to 30° C. Theresulting solid was filtered and washed with ethyl acetate and vacuumdried yielding 40 gm of wet cake crude protriptyline hydrochloride offormula (5).

Purification of Protriptyline hydrochloride (5)

Crude protriptyline hydrochloride (5) 40.0 gm was charged into a 500 mlsingle neck flask. 160 mL of toluene was added. The slurry was heated to80° C. to 85° C. and stirred for 60 minutes. The reaction mass wascooled to room temperature and the solid was filtered off and washedwith acetone. The product was dried at 70° C. under vacuum for 15-20hours to afford white color solid (40.0 gm).

40.0 gm of the above dried product was charged into a 500 ml single neckflask. 200 mL of acetone was added and the slurry was heated to refluxtemperature and stirred for 60 minutes. The reaction mass was cooled toroom temperature and the solid was filtered off and washed with acetone.The product was suck dried well to afford white color wet cake (35.0gm).

35.0 gm of the above prepared wet cake was charged into a 500 ml singleneck flask. 200 mL of acetone was added and the slurry was heated toreflux temperature and stirred for 60 minutes. The reaction mass wascooled to room temperature and the solid was filtered off and washedwith acetone. The product was suck dried well to afford white color wetcake (30.0 gm). The resulting wet cake was dried at 60° C. under vacuumfor 20 hours. After drying the 22.0 gm of dried protriptylinehydrochloride was unloaded. The dried protryptilene was substantiallypure, having a purity of greater than 99.9%.

While the preferred embodiments have been described and illustrated itwill be understood that changes in details and obvious undisclosedvariations might be made without departing from the spirit and principleof the invention and therefore the scope of the invention is not to beconstrued as limited to the preferred embodiment.

1. A process of preparing3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol comprising reacting5-dihydro dibenzocycloheptatriene with chloro propyl alcohol in thepresence of an excess of n-butyl lithium.
 2. The process of claim 1wherein the step of preparing3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol comprises using 4 eq. ofn-butyllithium and 1.05 eq. of 3-chloropropyl alcohol.
 3. A process ofpreparing a compound of formula (4)

comprising combining a compound of formula (3)

and methyl amine solution in a solvent selected from the groupconsisting of methanol, THF and water.
 4. The process in accordance withclaim 3 wherein a 2.0M solution of Methyl amine in methanol is employed.5. The process in accordance with claim 3 wherein a 2.0M solution ofMethyl amine in THF is employed.
 6. The process in accordance with claim3 wherein methyl amine in water is employed in a concentration of 15% orgreater.
 7. The process in accordance with claim 3 wherein a 15-30%solution of methyl amine solution in methanol is employed.